Primary pulmonary hypertension (PPH) is characterized clinically by elevated pulmonary artery pressures in the absence of a secondary cause. Endovascular occlusion in the smallest pulmonary arteries occurs by proliferation of cells and matrix, with thrombus and vasospasm. The average life expectancy after diagnosis is 2 to 3 years with death usually due to progressive right heart failure. Although most cases appear to be sporadic, -6% of cases exhibit an autosomal dominant mode of inheritance with markedly reduced penetrance. We have recently identified heterozygous gennline mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene in a subset of both familial and sporadic PPH cases. Interestingly, not everyone who carries a BMPR2 mutation develops the disease. Therefore, we hypothesize that there are other genes that modify development of the disease in those individuals carrying BMPR2 mutations. The overall aim of this proposal is to identify any gene(s) responsible for the genetic modification of the penetrance of primary pulmonary hypertension through the use of mouse models. A mutant mouse carrying an inframe deletion of a portion of the BMPR2 gene (BMPR2 aEzY'ML) will be analyzed for the development of pulmonary hypertension using measurement of right ventricular systolic pressure, right ventricular weight, and lung histology to determine presence of a phenotype. As hypoxia exposure is known to result in pulmonary hypertension, these mice will be exposed to chronic hypoxia to determine whether a BMPR2 mutation plays a role in the susceptibility to hypoxia-induced pulmonary hypertension. To determine other genes that may be genetic modifiers of murine pulmonary hypertension, a survey of inbred strains will be conducted in an effort to identify genetic differences in the susceptibility to hypoxia-induced pulmonary hypertension. Strains showing the largest differences in their response to hypoxia will be used to genetically map the gene(s) responsible. F1 animals produced from an inter stain cross will be used to generate F2 animals. DNA samples from the F2 animals will be used for a genome screen using a set of linked polymorphic markers to genetically map the location of the gene(s) responsible for the difference in susceptibility to hypoxia-induced pulmonary hypertension. Lastly, transgenic animals will be produced over expressing the serotonin transporter (5-HTT), Smad4, and TGF[3R2 on both a wild type background and the BMPR26E2KML background. Susceptibility to pulmonary hypertension under both normoxic and hypoxic conditions will be determined. By completion of these specific aims, we expect to identify genetic modifiers of murine pulmonary hypertension whose homologues can then be studied in the human form of the disease.